Method of producing N-substituted 2,6-dialkylmorpholines

ABSTRACT

The present invention relates to a process for the preparation of N-substituted 2,6-dialkylmorpholines of the formula I 
                         
in which R 1  and R 2 , independently of one another, are hydrogen, alkyl or cycloalkyl, or R 1  and R 2  together with the carbon atom to which they are bonded are a 5- to 14-membered carbocycle, and R 3  and R 4 , independently of one another, are alkyl or cycloalkyl, by reacting at least one carbonyl compound of the formula II
 
                         
in which R 1  and R 2  have the meanings given above, with at least one morpholine of the formula III
 
                         
in which R 3  and R 4  have the meanings given above, in the presence of hydrogen and at least one metal-containing catalyst, wherein the active component of the catalyst consists essentially of platinum group metals.

The present invention relates to a process for the preparation ofN-substituted 2,6-dialkylmorpholines by reacting a carbonyl compoundwith a secondary amine in a reductive amination.

Tertiary amines form an important class of compounds which is usedindustrially in extremely diverse sectors. There is therefore acontinuous need for the simplest possible processes which permit thepreparation of tertiary amines from very readily accessible componentsin high yields and with high selectivity toward the desired targetcompound. Among the heterocyclic tertiary amines, the N-substitutedtetrahydro-1,4-oxazines (morpholines) are used, for example, in cropprotect on.

K. H. König et al. describe, in Angewandte Chemie 77 (1965), pp.327–333, N-substituted tetrahydro-1,4-oxazines and the use thereof asfungicidal compounds with good action against fungal disorders ofcultivated plants. According to this, the preparation of these compoundscan, for example, be carried out by dehydrating cyclization of thecorresponding bis(2-hydroxyethyl)amines.

DE-A-25 43 279 likewise describes a process for the preparation ofN-substituted tetrahydro-1,4-oxazines by single- or two-stagecyclization and hydrogenation of N-substitutedbis(2-hydroxyalkyl)amines.

A disadvantage of the process given above is the complex preparation ofthe starting materials used.

DE-A-197 20 475 describes a process for the preparation ofN-alkyl-2,6-dialkylmorpholines in a two-stage synthesis, comprising thepreparation of an oxazolidine by reacting corresponding aldehydes orketones with dialcohols of secondary amines in the presence of an acidicion exchanger, and the subsequent reaction of the oxazolidine in thepresence of hydrogen and a hydrogenation catalyst.

The direct preparation of tertiary amines from carbonyl compounds andspecifically from ketones and secondary amines is generally difficultsince the target compounds are usually only obtained in low yields, andtheir isolation is accordingly laborious.

DE-A-33 21 712 describes 2,6-trans-dimethylmorpholine derivatives andthe use thereof as fungicides. According to this, the preparation ofN-(cyclododecyl)-2,6-dimethylmorpholine (dodemorph), for example, iscarried out in a two-stage synthesis, comprising the reaction ofcyclododecanone and 2,6-trans-dimethylmorpholine in the presence ofp-toluenesulfonic acid to giveN-cyclododecenyl-2,6-trans-dimethylmorpholine and the subsequenthydrogenation thereof in the presence of a Pd/C catalyst.

EP-A-0 271 750 describes fungicidal 4-substituted cyclohexylamines.These can be obtained, for example, by reductive amination ofcyclohexanones with a secondary amine in the presence of a reducingagent. Suitable reducing agents are hydrogen, formic acid and complexhydrides, such as sodium cyanoborohydride. Suitable catalysts for thereductive amination in the presence of hydrogen are not described. Thisreaction variant is not demonstrated by a working example either.

DE-A-21 18 283 describes a process for the preparation of secondary ortertiary aliphatic or cycloaliphatic amines by reacting an aliphatic orcycloaliphatic carbonyl compound with ammonia or a primary or secondaryamine in the presence of hydrogen and a hydrogenation catalyst, wherethe catalyst used is a mixture of silver and palladium on a sinteredsupport. A disadvantage of this process is the high costs of the silvercatalyst used. In addition, the resulting yields and the selectivitieswith regard to the target compounds are in need of improvement.

It is an object of the present invention to provide an improved processfor the preparation of N-substituted 2,6-dialkylmorpholines. In thisconnection, the synthesis is to take place starting from carbonylcompounds and secondary amines in a single-stage reaction. Preferably,the process should permit the preparation of tertiary amines in highyields and with high selectivity toward the desired target compounds.

We have now found, surprisingly, that this object is achieved by aprocess for the preparation of N-substituted 2,6-dialkylmorpholines, inwhich at least one carbonyl compound is reacted with at least onemorpholine derivative in the presence of hydrogen and at least onemetal-containing catalyst whose active component consists essentially ofplatinum group metals, in a reductive amination.

The invention thus provides a process for the preparation ofN-substituted 2,6-dialkylmorpholines of the formula I

-   -   in which    -   R¹ and R², independently of one another, are hydrogen, alkyl or        cycloalkyl, or R¹ and R² together with the carbon atom to which        they are bonded are a 5- to 14-membered carbocycle, and    -   R³ and R⁴, independently of one another, are alkyl or        cycloalkyl,        by reacting at least one carbonyl compound of the formula II

in which R¹ and R² have the meanings given above, with at least onemorpholine of the formula III

in which R³ and R⁴ have the meanings given above, in the presence ofhydrogen and at least one metal-containing catalyst, wherein the activecomponent of the catalyst consists essentially of platinum group metals.

For the purposes of the present invention, the expression “alkyl”includes straight-chain and branched alkyl groups. These are preferablystraight-chain or branched C₁–C₂₀-alkyl groups, preferably C₁–C₁₂-alkylgroups and particularly preferably C₁–C₈-alkyl groups and veryparticularly preferably C₁–C₄-alkyl groups. Examples of alkyl groupsare, in particular, methyl, ethyl, propyl, isopropyl, n-butyl, 2-butyl,sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, 3-methylbutyl,1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, n-hexyl, 2-hexyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl,2-ethylbutyl, 1-ethyl-2-methylpropyl, n-heptyl, 2-heptyl, 3-heptyl,2-ethylpentyl, 1-propylbutyl, octyl, nonyl, decyl.

Substituted alkyl radicals preferably have 1, 2, 3, 4 or 5, inparticular 1, 2 or 3, substituents. These are chosen, for example, fromcycloalkyl, aryl, hetaryl, halogen, OH, SH, alkoxy, alkylthio, NE¹E²,(NE¹E²E³)⁺, carboxyl, carboxylate, —SO₃H, sulfonate, nitro and cyano.

The cycloalkyl group is preferably a C₆–C₁₂-cycloalkyl group, such ascyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl or cyclododecyl.Particular preference is given to cyclohexyl and cyclododecyl.

If the cycloalkyl group is substituted, it preferably has 1, 2, 3, 4 or5, in particular 1, 2 or 3, substituents. These are chosen, for example,from alkyl, alkoxy, alkylthio, OH, SH, cycloalkyl, cycloalkylalkyl,nitro, cyano or halogen.

Aryl is preferably phenyl, tolyl, xylyl, mesityl, naphthyl, anthracenyl,phenanthrenyl, naphthacenyl and, in particular, phenyl or naphthyl.

Substituted aryl radicals preferably have 1, 2, 3, 4 or 5, in particular1, 2 or 3, substituents. These are chosen, for example, from alkyl,alkoxy, carboxyl, carboxylate, trifluoromethyl, —SO₃H, sulfonate, NE¹E²,alkylene-NE¹E², nitro, cyano or halogen.

Hetaryl is preferably pyrrolyl, pyrazolyl, imidazolyl, indolyl,carbazolyl, pyridyl, quinolinyl, acridinyl, pyridazinyl, pyrimidinyl orpyrazinyl.

Substituted hetaryl radicals preferably have 1, 2 or 3 substituentschosen from alkyl, alkoxy, carboxyl, carboxylate, —SO₃H, sulfonate,NE¹E², alkylene-NE¹E², trifluoromethyl or halogen.

The above statements regarding alkyl radicals apply correspondingly toalkoxy and alkylthio radicals.

The radicals NE¹E² are preferably N,N-dimethyl, N,N-diethyl,N,N-dipropyl, N,N-diisopropyl, N,N-di-n-butyl, N,N-di-tert-butyl,N,N-dicyclohexyl or N,N-diphenyl.

Halogen is fluorine, chlorine, bromine and iodine, preferably fluorine,chlorine and bromine.

For the purposes of this invention, carboxylate and sulfonate arepreferably a derivative of a carboxylic acid function or of a sulfonicacid function, in particular a metal carboxylate or sulfonate, acarboxylic or sulfonic ester function or a carboxamide or sulfonamidefunction.

The active component of the catalyst used according to the inventionconsists essentially of platinum group metals, i.e. Ru, Rh, Pd, Os, Ir,Pt and mixtures thereof.

Preference is given to using a catalyst whose active component isessentially free from silver.

Preference is given to the use of a catalyst whose active componentcomprises

-   -   1 to 100% by weight, preferably 10 to 99% by weight, of Pd,    -   0 to 60% by weight, preferably 1 to 55% by weight, of Pt, and    -   0 to 50% by weight, for example 0.1 to 40% by weight, of at        least one further metal, which is in particular chosen from Ru,        Rh, Os, Ir, Ce, La and mixtures thereof.

In the process according to the invention, preference is given to usinga catalyst which comprises a support. Suitable supports are verygenerally the customary support materials known to the person skilled inthe art. These include, for example, carbon-containing supportmaterials, such as activated carbon, silicon carbide, polymericsupports, metal supports, e.g. made of stainless steel, aluminum oxides,silicon dioxides, silicates, alumosilicates, such as zeolites, pumice,diatomaceous earth, silica gel, hydrotalcite, titanium dioxides,zirconium dioxides, zinc oxide, magnesium oxide and combinations andmixtures thereof. Where appropriate, the carrier materials can be dopedwith alkali metal and/or alkaline earth metal oxides. Particularpreference is given to using α-Al₂O₃, γ-Al₂O₃, SiO₂, TiO₂, ZrO₂ andmixtures thereof. Particular preference is given to ZrO₂. The supportscan generally have customary forms and can be used, for example, asextrudates (in the form of strands), pellets, beads, tablets, rings,saddles, woven fabric, knits, monoliths, spheres, powders, etc. For adiscontinuous process, use as powders is preferred.

The catalysts used can be prepared by generally known processes, forexample by impregnation of a support with solutions of compounds orcomplexes of the metals used. Suitable metal compounds (precursors) are,for example, metal salts, such as nitrates, nitrosyl nitrates, halides,carbonates, carboxylates, metal complexes, such as acetylacetonate,halogen complexes, e.g. chloro complexes, amine complexes etc. The metalcompounds can be applied to the support, for example, by commonprecipitation or impregnation. If two or more metal compounds are used,then these can be applied simultaneously or successively. In thisconnection, the order in which the active components are applied isusually unimportant. Suitable solvents for the preparation of thecatalysts by impregnation are water and organic solvents, such asalcohols, e.g. methanol and ethanol, aromatic compounds, such as benzeneand toluene, aliphatic solvents, such as hexane, heptane, etc.,cycloaliphatic solvents, such as cyclohexane, etc.

The preparation of supported palladium-containing catalysts ispreferably carried out by impregnating a support with a solution ofPd(NO₃)₂, PdCl₂, H₂PdCl₄, Pd acetylacetonate, etc.

Following impregnation, the support is preferably dried. The temperaturehere is generally in the range from about 50 to 200° C., preferably 100to 150° C. After drying, the support can be calcined if desired. Forthis, the temperature is generally in a range from 200 to 600° C.,preferably 400 to 500° C. The calcination time can vary within a widerange and is, for example, from about 1 to 10 hours, preferably 1.5 to 5hours. To convert the precursors into the active component, the catalystcan be treated with a customary reducing agent such as hydrogen. Duringthis treatment, inert gases, such as nitrogen or argon, can be mixedwith the reducing agent if desired. The temperatures during thereduction are preferably in a range from about 100 to 500° C.,particularly preferably 200 to 300° C. If, for the preparation of thecatalysts used according to the invention, a metal compound which isreadily thermally decomposable is used as precursor, then these areusually already decomposed to elemental metals or oxidic metal compoundsunder the calcination conditions, meaning that subsequent reduction isgenerally not required.

The drying and/or the calcination and/or the reduction can then befollowed by at least one further treatment step. These include, forexample, passivation, e.g. with oxygen, with which, where appropriate,at least one inert gas can be mixed. The passivation is preferably usedfor the preparation of catalysts based on metals for which the metaloxides also have catalytic activity.

Further processes for the preparation of catalysts which can be usedaccording to the invention are known to the person skilled in the artand include, for example, vapor deposition, sputtering, ion exchangeprocesses, etc.

According to a suitable embodiment, the catalyst is reduced in situ withhydrogen and thus converted into the active form.

The surface area, the pore volume and the pore size distribution of thecatalyst are uncritical within wide ranges.

In the process according to the invention, particular preference isgiven to using a catalyst which comprises 0.1 to 10% by weight of Pd,based on the weight of active component and support. The catalystpreferably comprises 0 to 5% by weight, such as, for example, 0.1 to 4%by weight, of Pt. Particular preference is given to catalysts whichcomprise only Pd as active component.

The process according to the invention permits, in an advantageousmanner, the single-stage preparation of N-substituted2,6-dialkylmorpholines. In the process, the target compounds aregenerally obtained in high yields and with high selectivity. The processaccording to the invention advantageously permits the preparation ofN-substituted 2,6-dialkylmorpholines even in cases of high startingmaterial feed rates, i.e. good space-time yields are generally achieved.A further advantage of the process according to the invention is thatthe isomerically pure preparation of N-substituted2,6-dialkylmorpholines is made possible.

Preferably, for the preparation of the N-substituted2,6-dialkylmorpholines, a ketone of the formula II is used in which R¹and R² together with the carbon atom to which they are bonded are a 6-to 12-membered carbocycle which may have one, two or three substituentswhich are chosen, independently of one another, from alkyl, alkoxy,alkylthio, cycloalkyl and cycloalkylalkyl. The compound of the formulaII is particularly preferably cyclododecanone.

Preferably, the radicals R³ and R⁴ in the formula III are, independentlyof one another, C₁–C₄-alkyl radicals. Particularly preferably, R³ and R⁴are both methyl.

The process according to the invention is particularly suitable for thepreparation of N-(cyclododecyl)-2,6-dimethylmorpholine (dodemorph).

The reaction temperature is preferably in a range from 100 to 300° C.

The reaction pressure is preferably 5 to 300 bar, particularlypreferably 10 to 250 bar.

The process according to the invention can be carried out without asolvent or in the presence of a solvent. Suitable solvents are water,alcohols, such as methanol and ethanol, ethers, such as methyltert-butyl ether, cyclic ethers, such as tetrahydrofuran, ketones, suchas acetone and methyl ethyl ketone, etc. The morpholine used as startingmaterial is particularly preferably used as solvent. In this connection,the morpholine can be used in an up to 100-fold molar excess relative tothe amine component.

The process according to the invention can be carried out batchwise orcontinuously. Preference is given to the continuous procedure.

Suitable reactors for carrying out the process according to theinvention are the customary apparatuses for working under increasedpressure known to the person skilled in the art, such as, for example,autoclaves or tubular reactors. The catalyst is preferably used in theform of a fixed bed or another suitable incorporation. The reactionspace is preferably arranged vertically.

The reaction preferably takes place on downward flow through thecatalyst bed or on upward flow through the catalyst bed. In thisconnection, the starting materials are preferably introduced such thatthe entire catalyst layer is essentially continuously covered withliquid.

The invention further provides for the use of a catalyst, as definedabove, for the preparation of a tertiary amine by reacting at least onecarbonyl compound with at least one secondary amine in the presence ofhydrogen.

The invention is described in more detail by reference to thenonlimiting examples below.

EXAMPLES Example 1 (Comparison Pd/Ag Catalyst)

500 ml of a catalyst which comprised 5% Ag₂O and 0.4% PdO on an SiO₂support were introduced into a vertical tubular reactor. At atemperature of 220° C. and a hydrogen pressure of 100 bar, a mixture,heated to 220° C., of one part of cis-2,6-dimethylmorpholine, one partof trans-2,6-dimethylmorpholine and 0.39 parts of cyclododecanone waspumped in from below at a feed rate of 360 ml/h.

The reaction mixture which emerged comprised, following removal of the2,6-dimethylmorpholine under reduced pressure, 89.6% of dodemorph and2.3% of cyclododecanone. This corresponds to a conversion of 97.3% and aselectivity of 91%.

Example 2 (Pd/ZrO₂ Catalyst)

The procedure was as in example 1, but using purecis-2,6-dimethylmorpholine and a Pd/ZrO₂ catalyst (palladium content0.9%). At the same temperature and feed rate and with removal of the2,6-dimethylmorpholine, the reaction mixture comprised 94.4% ofdodemorph and 0.7% of cyclododecanone. This corresponds to a conversionof 99.3% and a selectivity of 95%.

Example 3 (Pd/ZrO₂ Catalyst)

The procedure was as in example 2, but with double the feed rate (720ml/h) and a temperature of 240° C. Following removal of the2,6-dimethylmorpholine, the reaction mixture comprised 92.2% ofdodemorph and 2.6% of cyclododecanone. This corresponds to a conversionof 97.4% and a selectivity of 95%.

Example 4 (Pd/Pt, ZrO₂ Catalyst)

The procedure was as in example 1, but using purecis-2,6-dimethylmorpholine and a Pd/Pt/ZrO₂ catalyst (palladium content0.4%, platinum content 0.4%). At a temperature of 230° C. and a feedrate of 180 ml/h, the reaction mixture comprised, following removal ofthe 2,6-dimethylmorpholine, 95.6% of cis-dodemorph and nocyclododecanone. This corresponds to a conversion of 100% and aselectivity of 95%.

1. A process for the preparation of N-substituted 2,6-dialkylmorpholinesof the formula I

in which R¹ and R², independently of one another, are hydrogen, alkyl orcycloalkyl, or R¹ and R² together with the carbon atom to which they arebonded are a 5- to 14-membered carbocycle, and R³ and R⁴, independentlyof one another, are alkyl, or cycloalkyl, by reacting at least onecarbonyl compound of the formula II

in which R¹ and R² have the meanings given above, with at least onemorpholine of the formula III

in which R³ and R⁴ have the meanings given above, in the presence ofhydrogen and at least one metal-containing catalyst, wherein the activecomponent of the catalyst consists essentially of platinum group metalsand is essentially free from silver.
 2. A process for the preparation ofN-substituted 2,6-dialkylmorpholines of the formula I

in which R¹ and R², independently of one another, are hydrogen, alkyl orcycloakyl, or R¹ and R² together with the carbon atom to which they arebonded are a 5- to 14-membered carbocycle, and R³ and R⁴, independentlyof one another, are alkyl or cycloalkyl, by reacting at least onecarbonyl compound of the formula II

in which R¹ and R² have the meanings given above, with at least onemorpholine of the formula III

in which R³ and R⁴ have the meanings given above, in the presence ofhydrogen and at least one metal-containing catalyst, wherein the activecomponent of the catalyst comprises 1 to 100% by weight of Pd, 0 to 60%by weight of Pt, and 0 to 50% by weight of at least one further metal,which is chosen from Ru, Rh, Os, Ir, Ce, La and mixtures thereof.
 3. Aprocess as claimed in claim 1, wherein a catalyst is used whichcomprises a support.
 4. A process as claimed in claim 3, wherein thesupport used is ZrO₂.
 5. A process as claimed in claim 3, wherein acatalyst is used which comprises 0.1 to 10% by weight of Pd and 0 to 5%by weight of Pt.
 6. A process as claimed in claim 1, wherein R¹ and R²together with the carbon atom to which they are bonded are a 6- to12-membered carbocycle which can have one, two or three substituentswhich are chosen, independently from one another, from alkyl, alkoxy,alkylthio, cycloalkyl and cycloalkylalkyl.
 7. A process as claimed inclaim 1, wherein R³ and R⁴, independently of one another, areC₁–C₄-alkyl radicals.
 8. A process as claimed in claim 1, wherein R³ andR⁴ are both methyl.
 9. A process as claimed in claim 1 wherein thecompound of the formula I is N-(cyclododecyl)-2,6-dimethylmorpholine.10. A process as claimed in claim 4, wherein a catalyst is used whichcomprises 0.1 to 10% by weight of Pd and 0 to 5% by weight of Pt.
 11. Aprocess as claimed in claim 2, wherein a catalyst is used whichcomprises a support.
 12. A process as claimed in claim 11, wherein thesupport used is ZrO₂.
 13. A process as claimed in claim 12, wherein acatalyst is used which comprises 0.1 to 10% by weight of Pd and 0 to 5%by weight of Pt.
 14. A process as claimed in claim 11, wherein acatalyst is used which comprises 0.1 to 10% by weight of Pd and 0 to 5%by weight of Pt.
 15. A process as claimed in claim 2, wherein R¹ and R²together with the carbon atom to which they are bonded are a 6- to12-membered carbocycle which can have one, two or three substituentswhich are chosen, independently from one another, from alkyl, alkoxy,alkylthio, cycloalkyl and cycloalkylalkyl.
 16. A process as claimed inclaim 2, wherein R³ and R⁴, independently of one another, areC₁–C₄-alkyl radicals.
 17. A process as claimed in claim 2, wherein R³and R⁴ are both methyl.
 18. A process as claimed in claim 2, wherein thecompound of the formula I is N-(cyclododecyl) -2,6-dimethylmorpholine.